Nerve cell death is a gross neuropathologic feature associated with many neurodegenerative diseases. In the case of Alzheimer's disease (AD), deterioration of synaptic connections made by axons and dendritic processes has been linked to the loss of neurotrophic support in the brain centers affected by AD. Several experimental strategies and discovery schemes have been employed as a means to reverse the effects on neuronal architecture but many have not translated into successful therapies. Direct application of nerve growth factor (NGF) has been shown to augment morphological and sometimes functional recovery of degenerating neurons suggesting that a therapeutic approach that enhances the function of neurotrophins could halt or reverse the effects of AD and other neurodegenerative diseases. Our central hypothesis is that small molecules that enhance the activities of neurotrophins are uniquely suited to study the fundamental mechanisms that underlie activity potentiation of neuropeptides by drug-like chemicals in order to identify potentil targets that could lead to development of novel therapeutics for many age-related neurodegenerative diseases. Consequently, we have synthesized and tested Verbenachalcone (VC), a natural product from Verbena litoralis, and several derivatives that promote neurite outgrowth (NOG) in neuronal cell models. In addition, we utilized the dihydrochalcone backbone of VC as a template in a computational model to identify a small molecule B355252 with NGF-dependent NOG promoting activity and neuroprotective properties. Derivatives of the small molecule with improved toxicity profile have been synthesized. However, the SAR studies have not yielded improvements in compound potency. In this project we propose to identify compounds with novel scaffolds different from that of B355252, which synergize with NGF to enhance NOG by implementing a phenotypic image-based screen. In addition, we will develop and validate an in vitro blood- brain permeability assay to test the analogs and hits from the screen for potential to cross the blood-brain barrier and initiate studies on the signaling mechanisms of lead compounds as a prelude for future in vivo compound studies.